This is a phase I STTR application to study the efficacy of selective adenosine A2A receptor (A2AR) agonists developed in the laboratories of Adenosine Therapeutics (ATL) in models of Gram-positive bacterial sepsis which will be conducted in the University of Virginia (UVA) laboratories of Dr. Michael Scheld, an expert in the field of infectious disease. Sepsis syndrome is the 11th leading cause of death in the United States. Nearly 900,000 cases occur annually, resulting in 210,000 deaths, with 50% of sepsis cases due to Gram-negative pathogens such as S. aureus. While many new therapies targeting aspects of the inflammatory cascade have been tried, the results have been generally disappointing. We hypothesize that following the initiation of sepsis syndrome, selective adenosine A2A receptor (A2AR) agonists afford protection from tissue injury and the deleterious effects of inflammation by inactivating inflammatory hematopoeitic cells (neutrophils, monocytes, macrophages and T cells). This results in reduced neutrophil-endothelial cell interactions, thus abrogating the early cascade of pro-inflammatory cytokine release with an accentuation of an anti-inflammatory cytokine-chemokine response. We will specifically evaluate 1) the pharmacokinetics and formulation stability of 3 new, highly selective and potent A2AR agonists; 2) evaluate these compounds in a lethal murine model of sepsis using S. aureus; and 3) evaluate the cytokine profile of control and drug-treated animals to gain greater understanding of underlying mechanisms and signaling molecules in sepsis. These objectives directly relate to the mission of the National Institute of Allergy and Infectious Diseases, which is to conduct and support basic and applied research to better understand, treat, and ultimately prevent infectious, immunologic, and allergic diseases, by targeting drug development for gram-positive sepsis, for which current therapies are not ideal for patient care and survival. [unreadable] [unreadable] [unreadable]